Deoxyribonucleoside triphosphate pools and Ara-CTP levels in P388 murine leukemic cells treated with 1-B-D-arabinofuranosylcytosine-5'-stearylphosphate which is a newly synthesized derivative of 1-B-D-arabinofuranosylcytosine.
1-B-D-arabinofuranosylcytosine-5'-stearylphosphate (C18PCA), which is an Ara-CMP ester and one of the most promising orally effective anti-leukemic drugs, is a newly synthesized derivative of Ara-C. The antitumor effect of C18PCA and Ara-C was investigated against the P388 ascites tumor in BDF1 mice. Treatment with C18PCA (100 mg kg-1, orally) and Ara-C (40 mg kg-1, subcutaneously) was administered on days 1, 3 and 5 after tumor inoculation. The percentage increase in lifespans of the mice treated with C18PCA or Ara-C were 84.4% and 53.9%, respectively. The determination of the plasma Ara-C concentration revealed that the plasma concentration of Ara-C was retained much longer in mice which orally received C18PCA than in those which received Ara-C. By using high-performance liquid chromatography, it was revealed that the deoxyribonucleoside triphosphate pools increased gradually but Ara-CTP concentration once increased, then decreased rapidly when Ara-C was administered subcutaneously. On the other hand, both the intracellular deoxyribonucleoside triphosphate (dNTP) pools and Ara-CTP level increased gradually after oral administration of C18PCA. We concluded that these longer-term biochemical effects, even if the plasma concentration of Ara-C and Ara-CTP level were low, might be correlated with antitumor effects of C18PCA.
Higashigawa
M
M
Department of Pediatrics, Mie University School of Medicine, Japan.
Hori
H
H
Ohkubo
T
T
Kawasaki
H
H
Yoshizumi
T
T
Sakurai
M
M
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism*; D001088:Arabinonucleotides / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003561:Cytarabine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D003568:Cytidine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D003854:Deoxyribonucleotides / Q000378:metabolism*; D007941:Leukemia P388 / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D051379:Mice
D000970:Antineoplastic Agents; D001088:Arabinonucleotides; D003854:Deoxyribonucleotides; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; C061162:1-arabinofuranosylcytosine-5'-stearylphosphate; D003568:Cytidine Monophosphate